Abstract
We report a new method for the preparation of chiral 2-aryl-2-fluoropropanoic acids, including 2-fluoroibuprofen, a fluorinated analogue of non-steroidal anti-inflammatory drugs (NSAIDs), by the kinetic resolution of racemic 2-aryl-2-fluoropropanoic acids using enantioselective esterification. By applying pivalic anhydride (Piv2O) as a coupling agent, bis(α-naphthyl)methanol [(α-Np)2CHOH] as an achiral alcohol, and (+)-benzotetramisole (BTM) as a chiral acyl-transfer catalyst, a series of racemic 2-aryl-2-fluoropropanoic acids were kinetically separated to afford the optically active carboxylic acids and the corresponding esters with good to high enantiomeric excesses. This technology can provide a convenient approach to furnish the chiral α-fluorinated drugs containing quaternary carbons at the α-positions in the 2-aryl-2-fluoropropanoic acid structure.
Highlights
Fluorinated compounds have grown in use in medicinal chemistry, because the insertion of a fluorine atom can dramatically change the metabolism, activity, and other properties of a compound [1]
The 2-aryl-2-fluoropropanoic acids, such as 2-fluoroibuprofen, a fluorinated analogue of non-steroidal anti-inflammatory drugs (NSAIDs), have been frequently synthesized by several groups [3,4,5,6,7,8,9,10,11,12,13], because the substitution of a fluorine atom for a hydrogen atom at the α-positions in the 2-aryl-2-fluoropropanoic acids prohibits the unwanted epimerization of NSAIDs, which converts them from the biologically active chiral forms to less active epimerized forms in vivo [14,15,16]
In order to evaluate the effectiveness of the kinetic resolution, we used a selectivity factor (s-value), which shows the ratio of reactivities of the (R)- and (S)-carboxylic acids [20]
Summary
Fluorinated compounds have grown in use in medicinal chemistry, because the insertion of a fluorine atom can dramatically change the metabolism, activity, and other properties of a compound [1]. With this trend, an increasing number of strategies for the syntheses of fluorinated drugs, which include the chiral quaternary carbons bonding with a fluorine atom, has been established [2]. Previous studies for the preparation of chiral 2-aryl-2-fluoropropanoic acids (asymmetric fluorination, optical resolutions) and our kinetic resolution system
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